The invention relates to methods of using matrix metalloproteinase inhibitors in glaucoma filtering surgery and in the treatment of ischemic damage to the retina and optic nerve.
The retina is comprised of a network of light sensitive nerve cells that line the back of the eye. Located at the innermost cell layer are the ganglion cells. Long filamentous extensions from the axons of these cells wind their way across the retinal surface to a central location at the back of the eye, where they turn and bunch together to form the optic nerve leading to the brain. Light-induced signals are transmitted to produce our perception of sight. The place where the axons turn is called the optic nerve head. The term glaucoma describes a group of diseases that involve optic nerve damage at the level of the optic nerve head. Glaucoma results in a progressive loss of sight and may eventually lead to blindness.
Elevated intraocular pressure (IOP) is the major risk for patients who suffer from glaucoma. In a normal subject""s eye, a fluid, known as the aqueous humor, circulates freely through the anterior chamber of the eye. This fluid, which is continuously produced by the eye""s ciliary body, is drained from the eye, through the trabecular meshwork, back into the bloodstream. When the fluid drains properly, an appropriate fluid pressure is maintained in the anterior chamber, maintaining the shape of the cornea. Elevated IOP develops when the filtration mechanism of the trabecular meshwork is no longer adequate, leading to an increase in fluid within the anterior chamber. This increase in fluid, in turn, leads to an increase in the IOP. It is this increase in IOP that subsequently causes pressure on the optic nerve at the level of the optic nerve head. This causes damage to the optic nerve, which, in turn, may lead to blindness.
Ischemia is defined as an arrest of blood flow and reduction of oxygen supply to a tissue or organ. Ischemic damage to the retina is a common pathological factor in a number of diseases which cause blindness in humans, including central retinal artery and vein occlusions, diabetes, retinopathy of prematurity, and glaucoma, among others. Occlusion or damage to vessels that supply blood and oxygen to the retina results in ganglion cell death and irreversible blindness.
Management of glaucoma is directed at the control of IOP. However, therapy that prevents damage at the optic nerve head and the death of ganglion cells would constitute a more direct treatment. Present information supports the working hypothesis that ganglion cell death in glaucoma may result from a particular form of ischemia. Support for this view comes from the observation that ischemia induced by occlusion of the retinal artery due to acute elevation of IOP in animals produces damage at the optic nerve head similar to that seen in glaucoma.
Presently, glaucoma is not curable by any available treatment method. However, a variety of different treatment options are available to control, and, perhaps, to slow, the progression of the disease. The choice of a particular treatment is often dependent upon the degree of progression of the disease. Possible treatment options include medicinal therapy, laser eye surgery, and/or conventional surgical methods. Although many different surgical techniques have been employed in the past, glaucoma filtering surgery, also known as trabeculectomy, is principally performed today for the surgical (i.e., non-laser) management of glaucoma. Glaucoma filtration surgery, also known as glaucoma filtering surgery (xe2x80x9cGFSxe2x80x9d) is typically, but not necessarily, performed on patients in whom prior medicinal and laser therapies have failed to reduce the IOP to sufficiently lower levels.
Generally, GFS is performed to control the IOP when medical therapy or other measures fail. Filtration surgery lowers the IOP by creating a fistula between the anterior chamber and the subconjunctival space, creating a filtering bleb. The aqueous humor that percolates through the bleb can then either be absorbed through veins or conjunctival lymphatics or, in some cases where the conjunctiva is thin, pass directly into the tear film. The major determinant of glaucoma filtering surgery success is the conjunctival wound healing response, with excessive post-operative scarring leading to filtration failure. Late bleb leaks may compromise the ability of the bleb to regulate IOP, and can lead to bleb-related complications, such as infection and hypotony. Current modalities to treat bleb leaks include the use of aqueous suppressants (Pederson,. Ocular hypotony. St. Louis: Mosby; 1989), use of soft bandage contact lenses, pressure patching, glaucoma tamponade shell (Joiner et al., A modification of the use of the glaucoma tamponade shell, OPHTHAL SURG 1989;20:441-2), application of trichloroacetic acid (Gehring et al., Trichloroacetic acid treatment of filtering blebs following cataract extraction, AM J OPHTHALMOL 1972;74:622-4), cyanoacrylate glue (Awan et al., Use of isobutyl-2-cyanoacrylate tissue adhesive in the repair of conjunctival fistula in filtering procedures for glaucoma, ANN OPHTHALMOL 1974;6:851-3; Weber et al., The use of-cyanoacrylate adhesive with a collagen shield in leaking filtering blebs, OPHTHAL SURG 1989; 20:284-5), autologous blood injection (Wise, Treatment of chronic postfiltration hypotony by-intrableb injection of autologous blood, ARCH OPHTHALMOL 1993; 11:827-30.), application of argon laser (Hennis HL, Stewart WC. Use of the argon laser to close filtering bleb leaks, GRAEFES ARCH CLIN EXP OPHTHALMOL 1992;230:537-41), and suturing of the blebs. A variety of surgical procedures have also been used to repair leaking late-onset blebs, including conjunctival patch grafts (Wilson et al., Free conjunctival patch for repair of persistent late bleb leak, AM J OPHTHALMOL 1994; 117:569-74.), and scleral patch grafts in association with conjunctival advancement (Melamed et al., Donor scleral graft patching for persistent filtration bleb leak, OPHTHAL SURG 1991;22:164-5; Morris et al., Use of autologous Tenon""s capsule and scleral patch grafts for repair of excessively draining fistulas with leaking filtering blebs, J GLAUCOMA 1998;7:417-9; O""Connor et al., A surgical method to repair leaking filtering blebs, OPHTHAL SURG 1992;23:336-8; Dunnington, Late fistulization of operative wounds. Diagnosis and treatment, ARCH.OPHTHALMOL.1950;43:407-418). Successful closure of late-onset bleb leaks often requires surgical revision of the bleb (Ritch et al., Cases in controversy: Management of the leaking filtration bleb, J GLAUCOMA 1993;2:114-118).
The filtration surgery technique is designed to provide an alternative pathway for the aqueous humor fluid to leave the eye. More specifically, during filtration surgery the filtering or conjunctival bleb is created which serves as an auxiliary xe2x80x9cdrainxe2x80x9d on the outside of the eyeball, and which has direct communication to the inside of the eyeball. This alternate pathway has a lower resistance to fluid outflow than that of the failing, or irreversibly obstructed, trabecular meshwork found in the glaucoma patient. The desired result of this technique is to achieve a lower IOP that is compatible with normal optic nerve function.
Because the basic early events of GFS wound healing have not been well described in humans, animal models have been used to delineate the initial stages of wound healing process. Despite a number of studies using animal models and human tissues, however, the early events of wound healing after GFS are still not clearly understood. In the context of general wound healing, observations in animal models and after GFS in humans suggest a sequence of events in GFS wound healing that occur in early bleb failure. Wound healing has been shown to involve an orderly series of events, including ECM degradation, cell migration, matrix synthesis, and tissue remodeling. After surgical trauma to the conjunctiva, episclera, and iris, blood vessels-constrict, and leakage of plasma proteins (including fibrinogen, fibronectin, and plasminogen) and blood cells occurs. Fibroblasts proliferate and migrate from the wound edges after GFS and-subsequently synthesize fibronectin, interstitial collagens, and glycosaminoglycans to form fibrovascular tissue, and later this tissue is remodeled to form a dense collagenous subconjuctival scar with scattered fibroblasts and blood vessels leading to wound scarring and filtration failure. In an animal model of conjunctival scarring, recombinant anti-TGF-beta2 treatment significantly improved glaucoma filtration surgery outcome compared to control (Cordeiro et al., Human Anti-Transforming Growth Factor-beta 2 Antibody: A New Glaucoma Anti-Scarring Agent, INVEST OPTHAMOL VIS SCI 1999; 40:2225-34). Mitomycin C and 5-fluorouracil are widely used as antiproliferative agents to inhibit fibroblast activation (Stamper et al., Hypotonous maculopathy after trabeculectomy with subconjunctival 5-fluorouracil, AM J OPHTHALMOL 1992;1 14:544-53; Parrish et al., xe2x80x9cLate endophthalmitisxe2x80x9dxe2x80x94filtering surgery time bomb? OPHTHALMOLOGY 1996; 103:1167-8; Greenfield, Bleb-related ocular infection. J GLAUCOMA 1998;7:132-6). A complication of the use of these agents is the production of thin, avascular blebs with an increased incidence of wound leak, hypotony and endophthalmitis. In addition, recent studies suggest that mitomycin C and 5-FU, in addition to their antiproliferative effects, induce fibroblast apoptosis (Crowston et al., Antimetabolite-induced apoptosis in Tenon""s capsule fibroblasts, INVEST OPHTHALMOL VIS SCI 1998;39:449-54).
Early onset bleb leaks generally occur within a few months of surgery, and these leaks largely dependent on the technical aspects of the wound closure. In contrast, late-onset leaks are typically associated with thin, avascular blebs and generally occur months to years after the surgical procedure. In addition, a higher frequency of bleb-leaks is associated with mitomycin C treatment. Although mitomycin C is a widely used anti-proliferative agent, recent studies suggest that it leads to death of subconjuctival and scleral fibroblasts as well as vascular endothelial cells. This explains to some extent that mitomycin C may inhibit angiogenesis through a toxic effect on vascular endothelial cells and pleuripotent limbal stem cells, and may explain the high frequency of clinically avascular blebs seen after trabeculectomy with mitomycin C (Rubinfeld et al., Serious complications of topical mitomycin-C after pterygium-surgery, OPHTHALMOLOGY 1992;99:1647-54). The conjunctival wound healing in glaucoma filtration surgery is greatly influenced by the passage of aqueous through the surgical site. This is because of the presence of a number of cytokines, proinflammatory molecules, angiogenesis inhibitors, and plasminogen.
Late bleb leaks are more common in thin, avascular blebs, which occur more frequently with the use of adjunctive anti-metabolites (Greenfield et al., Late-onset bleb leaks after glaucoma filtering surgery, ARCH OPHTHALMOL 1998;1 16:443-7), or after full-thickness procedures (Le Guilloux, Glaucoma in the elderly, SOINS GERONTOL 1998:16-8). Recent studies suggest that a significant proportion of glaucoma filtering surgeries performed with antifibrosis agents such as mitomycin C, are associated with increased number of late-onset bleb leaks (Wilensky, Management of late bleb leaks following glaucoma filtering surgery, TRANS AM OPHTHALMOL SOC, 1992;90:161-8). The regulation of extracellular matrix (ECM) deposition is a key event in many physiological and pathological conditions. It is required for normal wound healing where synthesized ECM molecules replace mature connective tissue in remodeling. Excessive deposition or degradation of the remaining ECM, however, leads to pathological consequences. A tight balance between connective tissue synthesis and breakdown, is therefore, required for the normal functioning of all tissues. Matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d), in part, control this tissue balance. MMPs are a family of ECM degrading enzymes that share common functional domains and activation mechanism. To date, more than 20 members of the MMP family have been identified. MMPs are synthesized as secreted or transmembrane pro-enzymes and processed in the active form by the removal of an amino-terminal pro-peptide in the extracellular space and are capable of degrading all the components of the ECM including fibrillar and non-fibrillar collagens, fibronectin, laminin and basement membrane glycoproteins (Wojtowicz-Praga et al., Matrix Metalloproteinase Inhibitors, INVEST NEW DRUGS 1997; 15:61-75). The family of MMP enzymes includes, but is not limited to, collagenases, gelatinases, matrilysin and stromelyin; all of which have been shown to be involved in the degradation and remodeling of connective tissues.
As previously stated, the major determinant of glaucoma filtering surgery (GFS) success is the conjunctival wound healing response, with excessive post-operative scarring leading to filtration failure. Late bleb leaks may compromise the ability of the bleb to regulate IOP, and can lead to bleb-related complications such as infection and hypotony. Successful closure of late onset bleb leaks often requires surgical revision of the bleb.
GFS differs from most surgical procedures in that inhibition of wound healing is desirable to achieve surgical success. Successful filtration surgery is generally characterized by formation of a filtering bleb, which is a subconjunctival accumulation of aqueous. Histopathological examinations of functioning blebs demonstrate the appearance of loosely arranged connective tissue beneath the conjunctival epithelium. Early failed blebs demonstrate abnormally thickened, dense collagenous connective tissue beneath the conjunctival epithelium. In contrast, late failing blebs are often thin, and avascular.
Additional information regarding glaucoma filtering surgery is provided in R. Rand Allingham, xe2x80x9cFiltering Surgery in the Management of Glaucoma,xe2x80x9d in Chandler and Grant""s Glaucoma 4th Ed., Williams and Williams Eds., pp. 516-25 (1997), which is hereby incorporated by reference.
While surgical repair of leaking filtering blebs remains a treatment option, other improved and less invasive treatments for leaking filtering blebs, as well as treatment for ischemic damage of the retina and optic nerve would likely be widely accepted.
Leaks in the conjunctival filtering blebs may occur as either an early or late complication of glaucoma filtering surgery. These leaks decrease the ability of the glaucoma filtering surgery to regulate IOP and to control glaucoma symptoms.
Accordingly, in one aspect, the instant invention describes a method for the inhibition, prevention, and/or treatment of conjunctival bleb leaks.
Also provided is a method of inhibiting, preventing, and/or treating optical nerve damage in glaucoma patients.
More specifically, in one aspect, the present invention involves the use of pharmacologically effective, oral or topical, doses of a matrix metalloproteinase inhibitor to block excessive MMP activity in the blebs of patients who have undergone glaucoma filtering surgery. More specifically, the instant invention involves the use of tetracycline, or one of its analogues possessing MMP inhibitor activity, in patients who have undergone glaucoma filtering surgical treatment.
In another aspect, the present invention involves the use of a pharmacologically effective, topical, eye drop form of an MMP inhibitor to block unwanted MMP activity in retinas of patients who have ischemic damage to the retina and optic nerve. More particularly, the invention involves the use of tetracycline, or one of its analogues possessing MMP inhibitor activity, in patients who have ischemic damage to the retina and optic nerve.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference.